The translational goal of this project is to conduct mechanistic studies on a novel molecular switch between PI3K/AKT and PDPK1/TORC that could lead to resistance to PI3K and AKT inhibitors; and of amino acid forms of mutant KRAS that activate different downstream signaling pathways that could lead to resistance to specific therapies and then two novel clinical trials with PI3K, AKT and MEK inhibitors, namely 1) an adaptively randomized multiarm targeted Phase II clinical trial and 2) a post-treatment biopsy Phase II trial of the AKT inhibitor MK-2206 in PTEN negative and positive CRC. The hypothesis to be tested in this proposal is that the phosphatidylinositol 3-kinase (PI3K) and RAS signaling pathways play major roles in CRC development and when aberrantly regulated make CRC resistant to many new molecularly targeted therapies. Three specific aims are proposed to test this hypothesis, and include: 1) determine the mechanisms of alternate pathways of PI3K signaling for sensitivity and resistance to targeted therapy for CRC; 2) determine the mechanisms of alternate downstream signaling by different amino acid-substituted forms of mutant KRAS for sensitivity and resistance to targeted therapy for CRC; and 3) conduct clinical trials of inhibitors of AKT, PI3K, and mut-KRAS signaling in patients with advanced CRC using patient tumor biopsy results to identify potential biomarkers for selecting patients with CRC for therapy. We will use a panel of CRC cell lines and isogenic mutant KRAS immortalized colonic epithelial cell lines in mechanistic studies in aims 1 and 2. Patient-derived CRC tumorgrafts will facilitate a direct comparison of tumor responses to drug treatment in vivo with patient response to therapy in aim 3. The long-term goal of this project is to develop an understanding of the mechanisms of resistance to therapy for CRC so that we can design more effective therapies, identify new drug targets for treatment, and develop biomarkers that identify CRC patients most likely to have responses to specific therapies.